Aloy

Araki

Beck

Coll

David Reverter

Del Rivero

Esther Berenguer

Fernández

Folk

Francesc X. Aviles

Gardell

Gerber

Gifty B. Barfi

Goodlad

Homandberg

Hooton

Javier Garcia-Pardo

Julia Lorenzo

Lufrano

Maria C. Garcia-Guerrero

Panosa

Peter J. Lyons

Robert Huber

Roberto Fernandez-Alvarez

Vendrell

Villegas

Significance
          Carboxypeptidase O (CPO) is a membrane-anchored brush-border enzyme associated with the small intestinal phase of protein digestion with distinctive specificity toward acidic C-terminal (C-t) amino acids. The combined activity of human CPO (hCPO) and pancreatic carboxypeptidases enables the C-t proteolysis of the great majority of amino acids present in dietary proteins. Here we disclose mechanism and structures of hCPO, both ligand-free and -bound with a natural peptidic inhibitor ascribing the exquisite specificity toward C-t acidic residues to a single amino acid, Arg275, in the substrate-binding pocket. Mutations of this residue to Asp and Ala suffices to reverse the specificity to C-t basic and hydrophobic residues, respectively, and faithfully mirror the specificity variants (hCPB, hCPA1, hCPA2) in enzyme kinetic assays.</jats:p

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Proceedings of the National Academy of Sciences

Crystal structure and mechanism of human carboxypeptidase O: Insights into its specific activity for acidic residues

Crystal structure and mechanism of human carboxypeptidase O: Insights into its specific activity for acidic residues

Abstract

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